This project seeks to assess the hidden associations linking toxic chemical exposure to human breast cancer via studies in mouse mammary tissues as well as both mouse and human cell lines. Studies correlate an increasing risk of breast cancer with increasing levels of alcohol consumption, but no causal relationship has been clearly established. Also, the effects of p-nitrophenol (an organophosphate pesticide derivative of methyl parathion) on the mechanisms responsible for the initiation of breast cancer have not yet been identified. The effects of exposure to either ethanol or p-nitrophenol will be examined to explain mechanisms for a possible association between alcohol consumption, pesticide exposure, and the development of breast cancer. The mechanisms we will examine involving these two chemical agents in relation to human breast cancer involve their potent induction of cytochrome P450, stimulation of 17-estradiol metabolism, DNA damage and modulation of expression levels of HMG-I (Y) DNA binding proteins. The research will examine these parameters in mouse and human mammary cell lines representing different degrees of breast cancer development as well as in untreated versus induced mouse mammary tissues in order to identify metabolic, endocrine and molecular biomarkers of breast cancer risk. Such indicators might allow the emergence of strong evidence for the mechanism(s) involved in both the observed ethanol induced increase in breast cancer incidence and the co-carcinogenic potential of pnitrophenol. Such approaches Aril I provide a testing method which may aid in targeting the most relevant subgroups of women or men whose risk of breast cancer might be affected by alcohol or toxic environmental U exposures. ItimateIN this information may lead to intervention prior to the expression of tumor phenotypes and may be expanded to identify other etiological agents and unexplained variables which have caused the escalating incidence of breast cancer in the United States and other industrialized nations.